PURPOSE: To examine the utility of electronic health records from a routine care setting in assessing comparative effectiveness of fourth-line anti-hypertensive drugs to treat resistant hypertension. METHODS: We conducted a cohort study using the Clinical Practice Research Datalink: a repository of electronic health records from UK primary care. We identified patients newly prescribed fourth-line anti-hypertensive drugs (aldosterone antagonist , beta-blocker, or alpha-blocker). Using propensity score-adjusted Cox proportional hazards models, we compared the incidence of the primary outcome (composite of all-cause mortality, stroke, and myocardial infarction) between patients on different fourth-line drugs. AA was the reference drug in all comparisons. Secondary outcomes were individual components of the primary outcome, blood pressure changes, and heart failure. We used a negative control outcome, Herpes Zoster, to detect unmeasured confounding. RESULTS: Overall, 8639 patients were included. In propensity score-adjusted analyses, the hazard ratio for the primary outcome was 0.81 (95% CI, 0.55-1.19) for beta-blockers and 0.68 (95% CI, 0.46-0.96) for alpha-blockers versus AA. Findings for individual cardiovascular outcomes trended in a more plausible direction, albeit imprecise. A trend for a protective effect for Herpes Zoster across both comparisons was seen. CONCLUSIONS: A higher rate of all-cause death in the AA group was likely due to unmeasured confounding in our analysis of the composite primary outcome, supported by our negative outcome analysis. Results for cardiovascular outcomes were plausible, but imprecise due to small cohort sizes and a low number of observed outcomes.